Substituted 1-methyl-1,2,3,4-tetrahydroisoquinoline molecules as pcsk9 allosteric binders

A compound of Formula I

• or a pharmaceutically acceptable salt thereof,
• wherein:
• RA is —C1-C6alkyl, —[OCH2CH2]mNRaC(O)RC, —(CH2)n-AryA1, —(CH2)n-HetA1 or —C1-C3alkylN3;
• wherein the —C1-C6alkyl or —C1-C3alkylN3 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkoxy, —C1-C6haloalkoxy, —C(O)ORa, —NRaRb and —OH;
• AryA1 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —CN, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —C(O)ORa, —CH(OH)C(NH2)C(O)ORa, —CH2OCH2CH2OCH3, AryA2, —(CH2)n-HetA1, —NRaRb and —OH;
• wherein the —C1-C6alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —ORa, —COORa, —C3-C6cycloalkyl, —C1-C4alkylCOORa, —NRaC(O)Rb, —NRaS(O)2Rb, —(CH2)n-AryA2, —OAryA2 and —NRaC(O)-AryA2,
• each occurrence of AryA2 is individually a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6haloalkyl-C1-C6alkoxy, —C1-C6haloalkoxy, —COORa, —CN, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —ORa, NRaRb, AryA3 and oxo;
• HetA1 is a 5-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from the group consisting of N and O, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C1-C6alkyl, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —ORa, —NRaRb, —CN and oxo;
• X1 and X2 are independently selected from the group consisting of N and CH;
• wherein if X1 is CH, X1 is optionally linked to RB through an —OC6-C7alkylene or an —OC6-C7alkenylene, wherein the O of the —OC6-C7alkylene or —OC6-C7alkenylene is bound at the X1 position;
• or alternatively X1 and X2 together with the ring atoms to which they are attached form a 5-6 membered aromatic monocyclic ring with 0, 1 or 2 heteroatom ring atoms independently selected from the group consisting of N and O, wherein said monocyclic ring is fused to the ring having X1 and X2, further wherein said monocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl and —C1-C6haloalkyl;
• Y is O or a bond;
• R1 is:
• 1) hydrogen,
• 2) halogen,
• 3) —C1-C6alkyl,
• 4) —C1-C6haloalkyl,
• 5) —C1-C6alkoxy,
• 6) —C1-C6haloalkoxy,
• 7) —C(O)ORa,
• 8) —C(O)NRaRb,
• 9) —CN,
• 10) CH2OH,
• 11) —SC1-C6alkyl,
• 12) —SO2Ra,
• 13) —SO2NRaRb,
• 14) —ORa,
• 15) —NRaRb,
• 16) —C(O)NRaAryA3, or
• 17) -AryA3;
• AryA3 is an aromatic 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N and O, wherein the 5-6 membered monocyclic ring or the 8-10 membered bicyclic ring are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6alkenyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —CN, —CH2OH, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —ORa, —C(O)ORa, —C(O)NRaRb, —C(O)NRaAryA4, —NRaC(O)AryA4, AryA4, —NRaRb, oxo and —OH;
• wherein the —C1-C6alkyl or the —C1-C6alkenyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C3-C6cycloalkyl, —C(O)ORa and —C(O)NRaRb;
• AryA4 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —CN, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —ORa and —NRaRb;
• each R2 is independently halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —CN, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, —ORa or —NRaRb;
• RB is -AryA5;
• wherein if X1 is CH, RB is optionally linked to X1 through an —OC6-C7alkylene or an —OC6-C7alkenylene, wherein the O of the —OC6-C7alkylene or —OC6-C7alkenylene is bound at the X1 position;
• AryA5 is an aromatic 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O and S, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —NRaRb, —CN, —CH2OH, —C(O)NRaRb, —SC1-C6alkyl, —SO2Ra, —SO2NRaRb, and —ORa;
• RC is —(CH2)p-adamantane, —(CH2)m-5,5-difluoro-1,3-dimethyl-5H-5λ4, 6λ4-dipyrrolo[1,2-c:2′,1′-j][1,3,2]diazaborinine, —(CH2)m-(3aR,6aS)-tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, —C1-C6alkyl and —C1-C2alkylene[OC1-C2alkylene]oC(O)NRaC1-C6alkyl;
• wherein the —C1-C6alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —NRaC(O)C1-C6alkyl, —NRaC(O)OC1-C6alkyl, —NRaC(═NC(O)ORb)(NRaC(O)ORb), —[OC1-C2alkylene]oC(O)NRaC1-C6alkyl and AryB1;
• wherein the —NRaC(O)C1-C6alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of —ORa, —NRaRb and AryB1;
• wherein the —C1-C2alkylene[OC1-C2alkylene]oC(O)NRaC1-C6alkyl is optionally substituted with a substituent selected from the group consisting of -HetB1 and —C(O)HetB1;
• HetB1 is a 5-membered saturated monocyclic ring with 1 N atom, optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C(O)NRa(CH2)n-AryB1 and —ORa;
• AryB1 is a 5-6 membered aromatic monocyclic ring with 0 or 1 N ring atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of AryB2, halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, —C(O)ORa, —NRaRb and —OH;
• AryB2 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N, O and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, and —ORa;
• Ra and Rb are independently H or C1-C6 alkyl;
• or alternatively Ra and Rb, if bound to the same atom, can together with the atom to which they are both attached form a —C3-C6cycloalkyl;
• each n is independently 0, 1 or 2;
• each m is independently 1, 2, 3 or 4;
• each o is independently 1, 2 or 3;
• and
• each p is independently 1, 2, 3 or 4.